Spinocerebellar ataxia 17 (SCA17) and Huntington’s disease-like 4 (HDL4). Giovanni Stevanin, Alexis Brice To cite this version: Giovanni Stevanin, Alexis Brice. Spinocerebellar ataxia 17 (SCA17) and Huntington’s disease-like 4 (HDL4).. The Cerebellum, Springer, 2008, 7 (2), pp.170-8. 10.1007/s12311-008-0016-1. inserm- 00293796 HAL Id: inserm-00293796 https://www.hal.inserm.fr/inserm-00293796 Submitted on 26 Mar 2009 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Stevanin & Brice, SCA7 and HDL4 1 SPINOCEREBELLAR ATAXIA 17 (SCA17) AND HUNTINGTON’S DISEASE-LIKE 4 (HDL4) GIOVANNI STEVANIN1,2,3 & ALEXIS BRICE1,2,3 1INSERM, U679, 75013 Paris, France; 2Université Pierre et Marie Curie – Paris 6, UMR S679, Institut Fédératif de Recherche en Neurosciences, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France; 3APHP, Groupe Hospitalier Pitié-Salpêtrière, Département de Génétique et Cytogénétique, 75013 Paris, France Correspondence: Giovanni Stevanin, PhD, INSERM U679, Groupe Pitié-Salpêtrière, 47 Boulevard de l’Hôpital, 75651 Paris Cedex 13, France. E-mail: [email protected] Running title: SCA7 and HDL4 Stevanin & Brice, SCA7 and HDL4 2 Abstract Spinocerebellar ataxia 17 (SCA17) or Huntington's disease-like-4 is a neurodegenerative disease caused by the expansion above 44 units of a CAG/CAA repeat in the coding region of the TATA box binding protein (TBP) gene leading to an abnormal expansion of a polyglutamine stretch in the corresponding protein. Alleles with 43 and 44 repeats have been identified in sporadic cases and their pathogenicity remains uncertain. Furthermore, incomplete penetrance of pathological alleles with up to 49 repeats has been suggested. The imperfect nature of the repeat makes intergenerational instability extremely rare and de novo mutations are most likely the result of partial duplications. This is one of the rarer forms of autosomal dominant cerebellar ataxia but the associated phenotype is often severe, involving various systems (cerebral cortex, striatum, and cerebellum), with extremely variable age at onset (range: 3-75 years) and clinical presentation. This gene is thought to account for a small proportion of patients with a Huntington’s disease- like phenotype and cerebellar signs. Parkinson’s disease-like, Creutzfeldt-Jakob disease-like and Alzheimer disease-like phenotypes have also been described with small SCA17 expansions. The abnormal protein is expressed at the same level as its normal counterpart and forms neuronal intranuclear inclusions containing other proteins involved in protein folding or degradation. The increase in the size of the glutamine stretch enhances transcription in vitro, probably leading to transcription deregulation. Interestingly, the TBP protein mutated in SCA17 is recruited in the inclusions of other polyglutaminopathies, suggesting its involvement in the transcription down- regulation observed in these diseases. Key words: Spinocerebellar ataxias, spinocerebellar degenerations, Huntington's disease, SCA17, HDL4 Stevanin & Brice, SCA7 and HDL4 3 Introduction Autosomal dominant cerebellar ataxias (ADCAs), often referred to as spinocerebellar ataxias (SCA), are a group of neurological disorders that are clinically and genetically highly heterogeneous (1). They are characterized by progressive cerebellar ataxia that results in uncoordinated movements, unsteady gait and dysarthria often associated with other neurological signs such as ophthalmoplegia, pyramidal or extrapyramidal signs, deep sensory loss and dementia. Onset is generally observed during the third or fourth decade but can also occur in childhood or old age. Neuropathologically, prominent atrophy of the cerebellum and brainstem is usually observed, but other structures may also be affected leading to a considerable range of phenotypes. Fifteen genes and their mutations have been identified. Translated (CAG)n/polyglutamine repeat expansions are responsible for the disease caused by 7 of these genes, SCA 1-3 (2-6), 6 (7), 7 (8-10), 17 (11) and dentatorubral-pallidoluysian atrophy (DRPLA) (12,13), and account for the vast majority of all ADCAs with a known genetic basis, although the precise frequency varies with geographical origin. Other genes with such mutations are unlikely to be identified. Two different studies using the Repeat Expansion Detection technique or the 1C2 antibody that recognizes large polyglutamines found no evidence of other disease-causing genes with large CAG repeats or proteins with polyglutamine expansions encoded by codons CAA or CAG (14,15). Indeed, the majority of newly identified forms, which represent only a small proportion of ADCAs, have non-coding repeat expansions or “classical” mutations in other genes. Non- coding repeat expansions have been reported at the SCA8 (16), SCA10 (17) and SCA12 (18) loci. More recently, mutations in the genes encoding fibroblast growth factor 14 [FGF14/SCA27, (19,20)], protein kinase C gamma [PKCG/SCA14, (21-28)], spectrin beta III [SPTBN2/SCA5, (29)] and potassium channel KCNC3 [SCA13, (30)] were also implicated in ADCA cases. In addition, a point mutation in the promoter region of a gene on chromosome 16 encoding Stevanin & Brice, SCA7 and HDL4 4 puratrophin-1, a new Rho GTPase protein, was found in 52 Japanese ADCA type III families (31). SCA17/HDL4 Spinocerebellar ataxia 17 (SCA17) or Huntington’s disease-like 4 (HDL4) is a rare neurodegenerative disorder (MIM#607136) that belongs to the group commonly referred to as “polyglutaminopathies” that also includes Huntington’s disease (HD), spinal and bulbar muscular atrophy and 6 other forms of ADCA (32). In the absence of treatment, they can all lead to dramatic neurological dysfunction and ultimately to death. The number of glutamines observed in the pathological proteins varies from 21 to >400 in the 9 diseases currently identified, but in most cases the phenotype manifests above a repeat number varying between 35 and 40. This class of disorders also shares, with few exceptions, other common clinical, genetic and physiopathological features suggesting common pathological mechanisms: i.e., a negative correlation between the size of the repeat expansion and the age at onset, anticipation with parental sex bias, instability of the repeat on expanded alleles and the formation of intranuclear inclusions in neurons. SCA17 was first reported in a sporadic case of a complex neurological disorder with cerebellar ataxia, pyramidal signs and severe intellectual impairment. This patient carried 63 trinucleotide repeats in the gene encoding the TATA-box binding protein (TBP) on chromosome 6q27 (11). This new genetic entity was subsequently identified in familial ADCA cases and was shown to differ in several aspects from other polyglutaminopathies (33-35). Pathological expansions were also found in patients with an HD-like phenotype (HDL4) or with clinical features compatible with Alzheimer, Parkinson’s or Creutzfeldt-Jakob disease, highlighting the clinical heterogeneity of this genetic entity (36-38). TATA-box binding protein Stevanin & Brice, SCA7 and HDL4 5 TBP is an important and general transcription factor ubiquitously expressed from a single gene on chromosome 6q27 and constitutes an integral component of the transcription initiation complexes of the 3 RNA polymerases (39-41). The TBP protein is the DNA-binding subunit of the RNA polymerase II transcription factor D (TFIID), a protein complex involved in mRNA transcription, and anchors the complex to the TATA box upstream of the first codon. The TBP protein also plays a role in TATA-less promoter genes by correctly positioning the polymerase on the DNA. Size and structure of the normal repeat in the TBP gene The N-terminus of the protein that modulates the DNA binding activity of the C-terminus (41), contains a long stretch of glutamines, as in other transcription factors or homeobox proteins (42). This repeat is impure and is encoded by 3 CAG stretches, interrupted by 1 to 3 CAA codons (Table 1). The glutamine stretch is polymorphic in the normal population and large population studies (>5000 control chromosomes) have determined that the normal range is between 25 to 42 residues, most alleles containing 32 to 39 repeats (11,33-35,37,40,43-45). The allelic distribution varies slightly, however, according to the ethnic/geographical origins (43,45). In a more recent Japanese study, alleles with up to 45 repeats were detected in the control population (38). Behaviour of the pathological expansions: range and incomplete penetrance Given its high polymorphism and the mean size of the repeat, which is above the pathological threshold of most polyglutamine diseases, the TBP gene was considered a good candidate gene for neurodegenerative and psychiatric diseases in which anticipation was suspected (40,45). An abnormally expanded CAG repeat (63 repeats) was initially described in a 14-year-old child with severe signs of ataxia and cognitive impairment without family history of neurological disorders (11). A series of studies world-wide subsequently reported familial